Beta-adrenergic signal transduction and contractility in the canine heart after cardiopulmonary bypass.
OBJECTIVE
Impaired beta-adrenergic signal transduction has been proposed as a mechanism contributing to myocardial depression after cardiac surgery. This study determined the changes in the beta-adrenergic system in a model of postoperative myocardial dysfunction induced by myocardial ischaemia and reperfusion under cardiopulmonary bypass (CPB). Those changes were then related to contractility and responsiveness to beta-adrenergic stimulation.


METHODS
Four groups of dog hearts were studied: 7 hearts harvested immediately after anaesthesia induction (control group representing the preoperative cardiac condition); 6 hearts harvested after three hours of chest opening by sternotomy (open chest group serving as control for the effects of anaesthesia and surgery); 7 hearts harvested during CPB after 30 minutes of global ischaemia (ischaemia group); and 10 hearts from dogs submitted to one hour of CPB involving 30 minutes of global cardiac ischaemia, harvested 30 minutes after CPB (ischaemia-reperfusion group). Myocardial membranes were prepared to assess: (1) beta-adrenergic receptor density using the radioligand [125I]iodocyanopindolol; (2) GTP-sensitive adenylate cyclase activity and its regulation by isoprenaline and forskolin; (3) G protein levels, using an immunoblotting technique. Ventricular trabeculae or papillary muscles served to assess contractility and responsiveness to isoprenaline.


RESULTS
The control and open chest groups had comparable beta-adrenergic receptor density, adenylate cyclase activity and cardiac contractility. In the ischaemia group, the left ventricular membranes had a 55% decrease in receptor density as compared to the controls (P < 0.005), similar GTP-sensitive adenylate cyclase activity and significantly lower adenylate cyclase responses to stimulation with isoprenaline and forskolin. In the ischaemia-reperfusion group, a 144% increase in the left ventricular receptor density was found as compared to the controls (P < 0.005), with a 70% increase in GTP-sensitive adenylate cyclase activity (P < 0.05), a similar adenylate cyclase response to isoprenaline and a 61% increase in response to forskolin (P < 0.005). As compared to the controls, the ischaemia and ischaemia-reperfusion groups had comparable Gs alpha levels, but markedly decreased Gi alpha-2 and Gi alpha-3 levels. The baseline tension of the isolated muscles in the ischaemia and ischaemia-reperfusion groups was comparable, but was 61% and 47% lower than the controls, respectively (P < 0.05). The maximal isoprenaline stimulated tension in the ischaemia and ischaemia-reperfusion groups was 66% and 36% lower than the controls, respectively (P < 0.05 between all groups).


CONCLUSIONS
The beta-adrenergic system is severely depressed during global cardiac ischaemia under CPB, but recovers to supranormal values after CPB. However the increased cAMP generation by myocardial membranes after CPB is associated with decreased tension generation by corresponding cardiac muscles. Thus decreased contractility after CPB may be better explained by cellular alterations distal to cAMP generation rather than by changes in the beta-adrenergic system.
Dupuis
J Y
JY
Department of Anaesthesia, University of Sherbrooke, Québec, Canada. jdupuis@heartinst.on.ca
Li
K
K
Calderone
A
A
Gosselin
H
H
Yang
X P
XP
Anand-Srivastava
M B
MB
Teijeira
J
J
Rouleau
J L
JL
D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002315:Cardiopulmonary Bypass; D002462:Cell Membrane / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D004285:Dogs; D019204:GTP-Binding Proteins / Q000378:metabolism; D015151:Immunoblotting; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000601:surgery; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D011184:Postoperative Period; D011869:Radioligand Assay; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol